Defect of mitotic vimentin phosphorylation causes microophthalmia and cataract via aneuploidy and senescence in lens epithelial cells.
Defect of mitotic vimentin phosphorylation causes microophthalmia and cataract via aneuploidy and senescence in lens epithelial cells.
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DOI：
10.1074/jbc.m113.514737
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发表时间：
2013-12-13
期刊：
影响因子：
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通讯作者：
Inagaki M
中科院分区：
文献类型：
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作者：
Matsuyama M;Tanaka H;Inoko A;Goto H;Yonemura S;Kobori K;Hayashi Y;Kondo E;Itohara S;Izawa I;Inagaki M
背景：波形蛋白是一种中间丝蛋白，在有丝分裂中被磷酸化。结果：细胞分裂过程中波形蛋白磷酸化的破坏导致小鼠透镜组织的染色体不稳定性（CIN）和过早老化。结论：我们的数据文件波形蛋白磷酸化在有丝分裂器官发生和组织稳态的第一个生理重要性。意义：我们的数据表明CIN和早衰之间可能存在因果关系。波形蛋白是一种III型中间丝蛋白，主要在有丝分裂中磷酸化。磷酸化受损波形蛋白突变体在T24培养细胞中的表达导致细胞动力学失败，导致双核化（多核化）。有丝分裂过程中中间丝磷酸化对器官发生和组织稳态的生理意义尚不确定。在这里，我们产生了敲入小鼠表达波形蛋白，有丝分裂过程中磷酸化的丝氨酸位点被丙氨酸残基取代。纯合子小鼠（VIMSA/SA）表现为小眼症和透镜中的白内障，而杂合子小鼠（VIMWT/SA）与WT小鼠（VIMWT/WT）无法区分。在VIMSA/SA小鼠中，透镜上皮细胞数量不仅减少，而且细胞还表现出染色体不稳定性，包括双核和非整倍体。电子显微镜检查显示VIMSA/SA晶状体中的纤维膜紊乱，这让人想起在年龄相关性白内障中观察到的类似特征性变化。由于衰老（老化）相关基因的mRNA水平在来自VIMSA/SA的样本中显著升高，因此透镜表型表明染色体不稳定性和过早老化之间可能存在因果关系。
Background: Vimentin, an intermediate filament (IF) protein, is phosphorylated in mitosis. Results: Disruption of vimentin phosphorylation during cell division leads to chromosomal instability (CIN) and premature aging in mouse lens tissue. Conclusion: Our data document the first physiological importance of vimentin phosphorylation during mitosis for organogenesis and tissue homeostasis. Significance: Our data suggest a possible causal relationship between CIN and premature aging. Vimentin, a type III intermediate filament (IF) protein, is phosphorylated predominantly in mitosis. The expression of a phosphorylation-compromised vimentin mutant in T24 cultured cells leads to cytokinetic failure, resulting in binucleation (multinucleation). The physiological significance of intermediate filament phosphorylation during mitosis for organogenesis and tissue homeostasis was uncertain. Here, we generated knock-in mice expressing vimentin that have had the serine sites phosphorylated during mitosis substituted by alanine residues. Homozygotic mice (VIMSA/SA) presented with microophthalmia and cataracts in the lens, whereas heterozygotic mice (VIMWT/SA) were indistinguishable from WT (VIMWT/WT) mice. In VIMSA/SA mice, lens epithelial cell number was not only reduced but the cells also exhibited chromosomal instability, including binucleation and aneuploidy. Electron microscopy revealed fiber membranes that were disorganized in the lenses of VIMSA/SA, reminiscent of similar characteristic changes seen in age-related cataracts. Because the mRNA level of the senescence (aging)-related gene was significantly elevated in samples from VIMSA/SA, the lens phenotype suggests a possible causal relationship between chromosomal instability and premature aging.